1. Field of the Invention
The present invention relates to a fluorescent dye-labeled glucose analogue, and a synthesis method and usage of the same, and more particularly, to a novel fluorescent glucose analogue labeled with fluorescent dye by O-1-glycosylation and via various linkers, a method for the synthesis thereof, and application thereof to molecular bioimaging and screening curative or preventive drugs for glucose metabolism-related diseases.
2. Description of the Related Art
Glucose is the most important energy source for cell growth; therefore, a fast-growing cancer cell requires more glucose than a normal cell. One of the biochemical markers of tumor malignancy is enhanced glycolysis due to the overexpression of glucose transporters (GLUTs) and the increased activity of hexokinases (phosphorylation catalytic enzyme of hexose) in tumors [M. Zhang, Z. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, B. Chance, J. D. Glickson, G. Zheng, Bioconjugate Chem. 2003, 14, 709-714].
The in vitro and in vivo assessment of glucose utilization has been of considerable interest to scientific communities, especially those in the biological and biomedical fields. One of the successful applications of this assessment is tumor diagnosis by positron emission tomography (PET) using a glucose probe of 18F 2-fluoro-2-deoxyglucose (18FDG) where 18F (fluoride) is used as an isotope that emits a positron [P. Som, H. L. Atkins, D. Bandoypadhyay, J. S. Fowler, R. R. MacGregor, K. Matsui, Z. H. Oster, D. F. Sacker, C. Y. Shiue, H. Turner, C. N. Wan, A. P. Wolf, S. V. Zabinski, J. Nucl. Med. 1980, 21, 670-675; H. Yorimitsu, Y. Murakami, H. Takamatsu, S. Nishimura, E. Nakamura, Angew. Chem. Int. Ed. 2005, 44, 2708-2711]. PET with 18FDG is a molecular imaging modality that monitors metabolic perturbation in tumor cells and allows the imaging of the exact positions of tumors in the human body; therefore, it is widely applied in the diagnosis of various tumors [P. S. Conti, D. L. Lilien, K. Hawley, J. Keppler, S. T. Grafton, J. R. Bading, Nucl, Med, Biol. 1996, 23, 717-735; J. Czernin, M. E. Phelps, Annu. Rev. Med. 2002, 53, 89-112.].
A fluorescent 2-deoxyglucose analogue, i.e., 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG), was developed and extensively studied, primarily by Yoshioka et al. [K. Yoshioka, H. Takahashi, T. Homma, M. Saito, K. B. Oh, Y. Nemoto, H. Matsuoka, Biochim. Biophys. Acta. 1996, 1289, 5-9.]. 2-NBDG has been widely applied in various studies, especially for tumor imaging and examination of GLUT-related cell metabolism [K. Yoshioka, H. Takahashi, T. Homma, M. Saito, K. B. Oh, Y. Nemoto, H. Matsuoka, Biochim. Biophys. Acta. 1996, 1289, 5-9; K. Yoshioka, M. Saito, K. B. Oh, Y. Nemoto, H. Matsuoka, M. Natsume, H. Abe, Biosci. Biotech. Biochem. 1996, 60, 1899-1901; A. Natarajan, F. Srienc, J. Microbiol. Methods. 2000, 42, 87-96]. In addition, some 2-deoxyglucose analogues have been reported [Z. Cheng, J. Levi, Z. Xiong, O. Gheysens, S. Keren, X. Chem, S. S. Gambhir, Bioconjugate Chem. 2006, 17, 662-669; Z. Zhang, H. Li, Q. Liu, L. Zhou, M. Zhang, Q. Luo, J. Glickson, B. Chance, G. Zheng, Biosensors and Bioelectonics. 2004, 20, 643-650; Y. Ye, S. Bloch, S. Achilefu, J. Am. Chem. Soc, 2004, 126, 7740-7741].
However, these analogues are all N-2-glycosylated analogues, and are disadvantageous in that a difference according to the type of α and β anomers of glucose cannot be confirmed, and that while D-glucose is an important energy source the cellular uptake of the analogues occurs only in a D-glucose-free medium, thus, it cannot be applied to test a cell in practice. Therefore, known 2-NBDG or N-2-glycosylated analogues cannot be used for screening anti-cancer drugs or therapeutics for obesity- or glucose metabolism-related diseases (e.g. diabetes).
Accordingly, the present inventors designed and synthesized novel glucose analogues labeled with fluorescent dye by O-1-glycosylation and via various linkers, unlike the known N-2-glycosylated glucose analogues.